The long-term goal of this project is to elucidate the cellular and molecular mechanisms by which statins protect against Alzheimer's disease (AD). Statins are a class of drugs that inhibit the biosynthesis of cholesterol. Currently, over 36 million Americans are taking statins to lower plasma cholesterol levels and prevent heart disease. Interestingly, while retrospective studies show a reduced prevalence of AD in people taking statins, prospective studies report mixed results. Thus, the discrepancy in the clinical data motivates new investigations to define the basic mechanisms through which statins affect cognitive function. That over 5 million people in the US are living with AD and have no satisfactory treatment available to slow down or reverse the disease underscores the great need to clarify the benefits of statin treatment for AD. This is further emphasized by the ongoing clinical trials such as Cholesterol-Lowering Agent (simvastatin) to Slow Progression (CLASP) of AD (ClinicalTrials.gov identifier: NCT00053599). While the beneficial effects of statins in AD are supported by studies showing that statins lower cholesterol levels and decrease amyloid-beta (AB) production, emerging evidence suggests that the protective effects of statins are beyond lowering cholesterol and AB levels. Recently, we have shown that simvastatin rescues learning and memory deficits in a mouse model of AD without affecting brain cholesterol and AB levels but increases phosphorylation of signaling molecules pertinent to memory formation and synaptic plasticity. Therefore, our working hypotheses are: a) statins exert the pro-synaptic/pro-cognitive effects by counteracting AB-induced toxicity and/or by directly modulating synaptic plasticity; b) the protective effects of statins are mediated by multiple pathways, most of which are independent of cholesterol; c) the efficacy of statins in decreasing AB levels depends on the stage of the disease at the initiation of the statin treatment as well as the choice and dose of statins; and d) direct neuronal effects may require the access of statins to the brain. These hypotheses will be tested by three specific aims using a combination of behavioral, electrophysiological, and biochemical approaches in vivo and in vitro: 1) To determine the efficacy of different statins in modulating AD-like behavior and pathology in a mouse model of AD. Three statins (simvastatin, atorvastatin, and rosuvastatin) that have different lipophilicity and blood-brain barrier (BBB) permeability will be evaluated. 2) To investigate the effect of statin treatment on synaptic plasticity in mouse hippocampal slices. Electrophysiological approaches will be employed to study the effect of statins on hippocampal synaptic plasticity. 3) To elucidate the cellular and molecular mechanisms by which statins exert protective effects. Depending on the findings from Aim 1 and 2, primary neuronal cultures will be used for more detailed mechanistic studies to define the cellular and molecular events by which statins exert their effects. Results from these studies will provide significant insight into the mechanisms by which statins protect against AD so that novel therapies may be developed to combat AD. PUBLIC HEALTH RELEVENCE: Emerging evidence indicates that statins, an effective medication for lowering cholesterol levels and preventing cardiovascular disease, are protective against the development of Alzheimer's disease (AD), a leading cause of dementia in elderly people. This project is designed to use a combination of behavioral, electrophysiological, and biochemical approaches to elucidate the cellular and molecular mechanisms by which statins exert anti-AD effects. Results from this project may lead to novel therapies to combat AD.